EP0123543B1 - Leukotrienantagonisten, deren Herstellung und Verwendung sowie diese enthaltende Zusammensetzungen - Google Patents

Leukotrienantagonisten, deren Herstellung und Verwendung sowie diese enthaltende Zusammensetzungen Download PDF

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Publication number
EP0123543B1
EP0123543B1 EP84302720A EP84302720A EP0123543B1 EP 0123543 B1 EP0123543 B1 EP 0123543B1 EP 84302720 A EP84302720 A EP 84302720A EP 84302720 A EP84302720 A EP 84302720A EP 0123543 B1 EP0123543 B1 EP 0123543B1
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Prior art keywords
thio
epsilon
hydroxy
erythro
oxo
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English (en)
French (fr)
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EP0123543A1 (de
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Robert N. Young
Haydn W. R. Williams
Joshua Rokach
Masatoshi Kakushima
Yvan Guindon
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Merck Frosst Canada and Co
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Merck Frosst Canada and Co
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
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    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention is concerned with antagonists of the slow-reacting substance of analphylaxis (SRS-A) and its major components, viz. the leukotrienes C 4 , D 4 and E 4 ; as well as of leukotriene B 4 .
  • SRS-A analphylaxis
  • SRS ⁇ A and the leukotrienes C 4 , D 4 and E 4 affect the smaller peripheral airways of the larger central passages such as the trachea and the bronchi.
  • these leukotrienes are manufactured from fatty substances trapped in the membrane of a triggered cell. A series of reactions within the cell generates this mixture of leukotrienes which may then pass through the cell membrane into the bloodstream. Once in the blood, these leukotrienes constrict air passages producing breathlessness.
  • Leukotriene 8 4 which is not part of SRS-A, is an important chemotactic factor which induces migration of polymorphic cells and thus contributes to both inflammatory and allergic diseases.
  • EP-Al-0 068 739 describes pharmacologically active compounds, useful in the treatment of allergic/inflammatory disorders involving SRS-A as causal mediator and which, in free acid form, are of formula I: in which
  • Y is ⁇ S ⁇ , -SO- or -S0 2 -, with the proviso that when -YR 2 is glutathionyl, cysteinyl or cysteinylglycinyl, the R 1 is other than an unsubstituted alkatetraenyl or alkapentaenyl radical of 12 to 16 carbon atoms.
  • This invention provides novel compounds of the Formula I: and compounds that are pharmaceutically acceptable salts thereof.
  • the various substituents are as defined below.
  • Compounds of the present invention are used as antagonists to prevent or reverse the actions of leukotrienes C 4 , D 4 and E 4 , and SRS-A and also leukotriene B 4 , and the present invention also provides.
  • pharmaceutical compositions containing such compounds and a pharmaceutical exciptent such as a diluent, carrier or coating.
  • the compounds of the present invention are useful in preventing and treating allergic conditions, such as chronic bronchitis, allergic rhinitis and asthma; skin diseases, such as psoriasis and atopic eczema; inflamation; and cardiovascular disorders such as angina.
  • each lower case letter represents an integer (or possibly 0) within the range stated, all values of variable radicals apply both when taken as part of another radical and when taken independently; and when a given variable appears more than once, the values of it can be the same or different. Where values of variable radicals in Formula II differ from those in Formula I, the values of variable radicals containing such radicals differ correspondingly.
  • lower alkyl means those aliphatic hydrocarbon groups of from 1 to 7 carbon atoms of either a straight, branched or cyclic configuration, and optionally having one or more double or triple bonds.
  • lower alkyl fragments include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and 2-butynyl.
  • alkyl includes aliphatic hydrocarbon groups having up to 20 carbon atoms in straight, branched or cyclic configuration, and optionally having one or more double or triple bonds, conjugated or unconjugated.
  • alkyl groups include octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl and 3,7-ethyl-2,2-methyl-4-propylnonyl.
  • aryl includes the carbon-containing aromatic structures such as phenyl, naphthyl, anthracenyl, phenanthrenyl and pyrenyl, optionally substituted with one or more alkyl groups.
  • heterocyclic rings mean 5 and 6 membered rings and bicyclic fused rings containing one or more O, N and/or S heteroatoms.
  • Generally useful heterocyclic rings include: where R is any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 .
  • halogen refers to F, Cl, Br and I.
  • the N-terminally bound essential amino acids are L-alanine, L-valine, L-leucine, L-isoleucine, L-proline, L-phenylalanine, L-tryptophan, L-methionine, L-glycine, L-serine, L-threonine, L-cysteine, L-tyrosine, L-asparagine, L-glutamine, L-lysine, L-arginine, L-histidine, aspartic acid and glutamic acid and the corresponding enantiomeric D-amino acids.
  • A represents where R 4 and R 5 are as defined above. It is particularly preferred that B is where the substituents are as defined above.
  • salts of the compounds described herein are included within the scope of the present invention.
  • Such salts may be prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic salts and the like. Particularly preferred are the potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, tri-methylamine, diethanolamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tomethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, imidazole, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, N,N'-dibenzylethylenediamine, piperidine, N-ethylpiperidine, morpholine, N-ethylmorpholine, polyamine resins and the like.
  • basic ion exchange resins such
  • the compound of Formula I are active as antagonists of SRS-A and the leukotrienes B 4 , C 4 , D 4 and E 4 .
  • This activity can be detected and evaluated by methods known in the art. See for example, Kadin, U.S. Patent U.S.-A-4,296,129.
  • the ability of the compounds of Formula I to antagonize the effects of the leukotrienes makes them useful for inhibiting the symptoms induced by the leukotrienes in a human subject.
  • the compounds are valuable therefore in the prevention and treatment of such disease states in which the leukotrienes are the causative factor, e.g. skin disorders, allergic rhinitis, and obstructive airway diseases.
  • the compounds are particularly valuable in the prevention and treatment of allergic bronchial asthma.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof can be administered to a human subject either alone, or preferably, on combination with pharmaceutically acceptable carriers or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • a compound can be administered orally or parenterally.
  • Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration, and also administration by inhalation and insufflation.
  • the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents are lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled to render the preparation isotonic.
  • the daily dosage will normally be determined by the prescribing physician. Moreover, the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms. However, in most instances, and effective daily dosage will be in the range from about 0.1 to about 40 mg per kg, and preferably 0.2 to 20 mg per kg, most preferably 1 to 10 mg per kg in a single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • compositions of the present invention can also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac, diflunisal and the like.
  • active ingredients such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac, diflunisal and the like.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • peripheral analgesic agents such as zomepirac, diflunisal and the like.
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the compound of the Formula I to the NSAID will generally range from about 200:1 to about 1:200. Combinations of a
  • the propionic acid derivatives which may be used comprise: ibuprofen, ibup ultrasound aluminum, indop-60, ketop antivirus, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid.
  • Structurally related propionic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be included in this group.
  • ⁇ CH(CH 3 )COOH or -CH 2 CH 2 COOH group which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH 3 )COO-Na + or ⁇ CH 2 CH 2 COO-Na + ), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
  • the acetic acid derivatives which may be used comprise: indomethacin which is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozic acid.
  • Structurally related acetic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
  • acetic acid derivatives as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH 2 COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g. -CH 2 COO-Na + ), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.
  • a free -CH 2 COOH group which optionally can be in the form of a pharmaceutically acceptable salt group, e.g. -CH 2 COO-Na +
  • fenamic acid derivatives which may be used comprise: mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid. Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
  • “fenamic acid derivatives” as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure: which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., ⁇ COO - Na + .
  • the biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and flufenisal. Structurally related biphenylcarboxylic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
  • biphenylcarboxylic acid derivatives as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure: which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO-Na +.
  • the oxicams which can be used in the present invention comprise: piroxicam, sudoxicam, isoxicam and 4-hydroxyl-1,2-benzothiazine 1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
  • oxicams as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which have the general formula: wherein R is an aryl or heteroaryl ring system.
  • NSAIDS may also be used: acemetacin, alminoprofen, amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen, cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetizole 'mesylate, fenclofenac, fenclorac, fendosal, fenflumizole, fentiazac, benz
  • NSAIDs designated by company code number, may also be used: 480156S, AA861, AD1491, AD1590, AFP802, AFP860, AHR6293, A177B, AP504, AU8001, BAYo8276, BPPC, BW540C, BW755C, CHINOIN 127, CN100, C0893XX, CPP, D10242, DKA9, DV17, EB382, EGYT2829, EL508, F1044, FZ, GP53633, GP650, GV3658, HG/3, ITCI, ITF, ITF182, KB1043, KC8973, KCNTEI6090, KME4, LA2851, LT696, LU20884, M7074, MED15, MG18311, MR714, MR897, MY309, N0164, ON03144, PR823, PV102, PV108, QZ16, R830, RS2131, RU16029,
  • NSAIDs which may also be used include the salicylates, specifically aspirin, and the phenylbutazones and pharmaceutically acceptable salts thereof.
  • compositions comprising the Formula I compounds may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in pending U.S. Patent Applications Serial Number 539,342, filed October 5,1983, Serial Number 459,924, filed January 21,1983 (corresponding EP Application 84300239.5), Serial Number 539,215, filed October 5, 1983, and Serial Number 547,161, filed October 31, 1983.
  • the compounds of the Formula I may also be used in combination with leukotriene antagonists such as those disclosed in copending applications U.S: Serial Nos. 520,051 and 520,052, filed August 5,1983 which are hereby incorporated herein by reference and others known in the art such as those disclosed in European Patent Application Nos. EP-A-56,172 and 61,800; and in U.K. Patent Specification No. GB-A-2,058,785.
  • compositions comprising the Formula I compounds may also contain as the second active ingredient, antihistaminic agents such as benadryl, dramamine, histadyl, phenergan and the like.
  • antihistaminic agents such as benadryl, dramamine, histadyl, phenergan and the like.
  • they may include prostaglandin antagonists such as those disclosed in European Patent Application EP-A 11,067 or thromboxane antagonists such as those disclosed in US-A-4,237,160.
  • They may also contain histidine decarboxyase inhibitors such as a fluoromethylhistidine, described in US ⁇ A ⁇ 4,325,961.
  • the compounds of the Formula I may also be advantageously combined with an H, or H 2 -receptor antagonist, such as for instance cimetidine, ranitidine, terfenadine, famotidine, aminothiadiazoles disclosed in EP 81102976.8 and like compounds, such as those disclosed in U.S. Patent Nos. US ⁇ A ⁇ 4,283,408; 4,362,736; 4,394,508; European Patent Application No. EP-A-40,696 and a pending application, U.S.S.N. 301,616, filed September 14, 1981.
  • the pharmaceutical compositions may also contain a K + /H + ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. US-A-4,255,431, and the like.
  • heteroaromatics A such as thiophene, furan and the like, may be reacted with a strong base, such as n-butyllithium.
  • a strong base such as n-butyllithium.
  • the resulting lithiated compound may then be reacted with an alkyl or alkenyl halide compound to produce the compound III.
  • Compound III may be reacted with a strong base, such as n-butyllithium, and the resulting lithiated species may be reacted with an omega-formyl alkanoic acid ester to yield a compound of Formula IV.
  • a strong base such as n-butyllithium
  • Compound V may be hydrolyzed by conventional means to yield the free acid compound of Formula VI.
  • Compounds of Formula IV may be treated with a catalytic amount of a strong acid, for example, p-toluenesulfonic acid, to eliminate water, thus forming an olefin. This olefin may then. be reacted with an epoxidizing agent, such as m-chloroperbenzoic acid, to provide an epoxide compound of Formula VII (Scheme 3).
  • a strong acid for example, p-toluenesulfonic acid
  • the epoxide compounds of Formula VII may be reacted with a thiol compound in the presence of a base such as triethylamine, sodium hydride, and the like, to yield a ⁇ -hydroxy sulfide compound of the Formula VIII.
  • a base such as triethylamine, sodium hydride, and the like.
  • the ⁇ -hydroxy sulfide compound VIII may be hydrolyzed by conventional means to provide the free acid compound of Formula IX.
  • a phenol of general Formula X (Scheme 5) may be reacted with dimethyl thiocarbamylchloride in the presence of a base such as triethylamine, sodium hydride and the like to yield the compound having general Formula XI.
  • Compound XI may be heated at from 150° to 250°C either neat or in a suitable solvent, to provide the compound of Formula XII.
  • Compound XII may be reacted with a base such as an alkoxide or hydroxide, and followed by acidification, generates the thiol compound having the Formula XIII.
  • Substituted aromatic compounds having the general Formula XIV may be reacted with oxalyl chloride in the presence of a Lewis Acid, such as aluminum chloride, to provide the acid chloride compound of Formula XV.
  • the acid chloride may be reduced by conventional means, for example by catalytic hydrogenation, to provide the aldehyde of general Formula XVI.
  • Aldehyde XVI may be reacted with a Wittig reagent of general Formula XVII to yield, following acidification, the olefin compound of Formula XVIII.
  • Substituted aromatic compounds of general Formula XIV may be reacted with an omega chloroformyl alkanoic acid ester or cyclic anhydride in the presence of a Lewis Acid, such as aluminum chloride to provide the ketone of general Formula XIX (Scheme 7).
  • a Lewis Acid such as aluminum chloride
  • Ketone XIX may be reduced using conventional techniques, for example, sodium borohydride, to provide the alcohol of general Formula IV.
  • Halogen (Cl, Br, I) substituted aromatic compounds of general Formula XX may be reacted with magnesium or lithium to generate the metalated species XXI.
  • the metalated species may be reacted with an omega-formyl alkanoic acid ester to provide the alcohol of general Formula IV (Scheme 8).
  • an alcohol of general Formula IV may be reacted with a phenol of general Formula X in the presence of a molar equivalent amount of diethylazodicarboxylate (DEAD) and triphenylphosphine to provide the ether compound of general Formula XXII.
  • DEAD diethylazodicarboxylate
  • triphenylphosphine triphenylphosphine
  • IR Infrared
  • NMR nuclear magnetic resonance
  • Examples 1-12 describe the preparation of intermediates used herein to prepare the novel compounds of Formula I.
  • the phenol from Step 3 (23 g) was hydrogenated in methanol (700 ml) under 50 psi H 2 pressure in the presence of 5% palladium on charcoal (2 g) for 1 hour.
  • the catalyst was removed by filtration over celite and the solvent was removed to provide the title compound, m.p. 160-162°.
  • Step 4 D,L-Erythro-epsilon-(2-carboxyethylthio)-delta-hydroxy-6-phenylhexanoic acid bis-(dicyclohexylammonium) salt
  • Step 2 The product from Step 1 (500 mg) was treated in a methanol (5 ml) with 0.204N NaOH (15.05 ml)
  • the ketone from Step 1 (9.19 g) was stirred in methanol (70 ml) and sodium borohydride (1.36 g) was added in portions. The mixture was poured into saturated NH 4 CI solution, and extracted with CH 2 CI 2 (3 x 100 ml). The organic phases were washed with water, dried (Na 2 SO 4 ) and reduced to dryness to provide the title compound as an oil.
  • the diester from Example 23 (1.9 g) was stirred in THF (41 ml) and 0.2N NaOH (41 ml) at ambient temperature for 18 hours. The mixture was concentrated in vacuo to remove the THF and applied to column of Amberlite XAD-8 resin and the column was washed with water until the effluent was neutral. Eluting with ethanol gave after concentration to dryness of the effluent, the title compound, m.p. 318° (decomp.).
  • Epsilon (S) and epsilon (R)-epsilon-(L-cysteinyl)-(4-n-nonylphenyl)hexanoic acid Step 1.
  • Step 1 Epsilon S and epsilon R-epsilon-N-trifluoroacetyl-L-cysteinylglycyl)-(4-nonylphenyl)hexanoic acid dimethyl ester
  • Step 2 Epsilon S and epsilon R-epsilon-cysteinylglycyl-(4-n-nonylphenyl)hexanoic acid disodium salt sesterhydrate
  • Step 1 D,L-methyl 7-(6-methoxy-4-oxo-1-(4-nonylphenyl)hexyloxy)-4-oxo-4H-1-benzo-pyran)-2-carboxylate
  • the diester from above (1 g) was dissolved in 18 ml THF and 18 ml 0.2N NaOH and stirred 48 hours under N 2 atmosphere. The mixture was reduced to dryness to provide the title compound, m.p. 225° (decomp.).
  • Step 1 A mixture of methyl D,L-(E)-delta,epsilon-epoxy-(4-n-nonylphenyl)hexanoate (550 mg), N-trifluoroacetyl-cysteinylglycine dimethyl ester (550 mg) and triethylamine (0.89 ml) in anhydrous methanol (5.5 ml) was stirred at ambient temperature under a nitrogen atmosphere 4 days. The mixture was evaporated to dryness and the residue was chromatographed on silica gel to provide the pure diasteriomers (absolute stereochemistry unassigned):
  • Step 2 The less polar diester from Step 1 above (338 mg) was stirred in methanol (2 ml) and 0.2N NaOH (9.4 ml) for 18 hours at ambient temperature. The mixture was concentrated in vacuo to near dryness, diluted with water (5 ml) and applied to a column of Amberlite XAD-8. After standing 1 hour, the column was washed with water until the effluent was neutral pH, then with 95% ethanol. The ethanol washings were reduced to dryness to provide isomer one of the title compounds, as an amorphous solid.
  • Step 3 Following the procedure described in Step 2 above, the more polar isomer from Step 1 was converted to isomer 2 of the title compounds, as an amorphous solid, obtained as mono-hydrate.
  • Step 1 Following the procedure described in Example 55, Step 1, but substituting an equivalent amount of D,L-(Z)-delta, epsilon-epoxy-(4-n-nonylphenyl)hexanoate for D,L-(E)-delta, epsilon-epoxy-(4-n-nonylphenyl)hexanoate was obtained a product 1 g which was stirred in toluene (5 ml) and trifluoroacetic acid (0.3 ml) for 2 hours.
  • Step 2 Following the procedure described in Example 54, Step 2, but substituting an equivalent amount of the lactone from Step 1 above, for (delta R, epsilon S) (or delta S, epsilon R)-delta-hydroxy-epsilon-S-(N-trifluoracetylcysteinylglycyl)-6-(4-n-nonylphenyl)hexanoic acid dimethyl ester, was obtained a product which was further purified by chromatography on silica gel eluting with methanol:chloroform:12N ammonium hydroxide (4:8:1) to provide the title compound, m.p. 100-104°.
  • Step 1 A mixture of the epoxide from Example 48, Step B, (1.44 g), 2-hydroxy-4-mercaptoacetophenone (0.556 g), triethylamine (1.85 ml) and anhydrous methanol (11 ml) was stirred 18 hours under an N 2 atmosphere at ambient temperature. The mixture was reduced to dryness and chromatographed on silica gel to provide methyl D,L-erythro-epsilon-((4-acetylhydroxyphenyl)thio)-delta-hydroxy-(4-n-nonylphenyl)-hexanoate as an oil.
  • Step 2 The ester from Step 1 (1.07 g) was stirred in THF (28 ml) and 0.2N NaOH (26 ml) for 18 hours at ambient temperature. The mixture was concentrated to remove THF and applied to a column of Amberlite XAD-8. After standing 1 hour, the column was washed with water until the effluent was neutral, then elution with 95% ethanol, and evaporation of the ethanol effluent gave the title compound, as a foam.
  • Step 1 A mixture of the epoxide from Example 48, Step B (0.82 g), 2-hydroxy-3-propyl-4-mercaptoacetophenone (0.58 g), triethylamine (1.4 ml) and anhydrous methanol (10 ml) was stirred 18 hours at ambient temperature. The solvents were removed in vacuo and the residue was chromatographed on silica gel to provide D,L-erythro-epsilon-((4-acetyl-3-hydroxy-2-propyl(2-n-propyl-3-phenyl)thio)-delta-hydroxy-(4-n-nonylphenyl)hexanoate as an oil.
  • Step 2 The ester from Step 1 (0.82 g), THF (16 ml) and 0.2N NaOH (16 ml) was stirred together at ambient temperature for 2 hours. The mixture was treated as described in Example 58, Step 2, to provide the title compound as a foam.
  • Step 1 A mixture of the epoxide from Example 48, Step B, (0.40 g), 2-hydroxymethyl-4-oxo-7-mercapto-4H-1-benzopyran (0.21 g), methanol (5 ml) and triethylamine (0.14 ml) was stirred together at ambient temperature for 3 days. The mixture was diluted with CH 2 CI 2 , washed with water, 0.01 N HCI and brine, then dried (Na 2 SO 4 ) and evaporated to dryness.
  • Step 2 A solution of the ester from Step 1 (0.696 g), THF (10 ml), and 0.2N NaOH (10 ml) was stirred for 5 minutes at ambient temperature. The mixture was treated as described in Example 58, Step 2. The resulting product was further purified by chromatography on C-18 silica gel, eluting with methanol-water, to provide the title compound, as a foam.
  • Step 1 A mixture of the epoxide from Example 48, Step B (0.945 g), 2-carbomethoxymethoxy-4-mercaptoacetophenone (0.787 g), triethylamine (1.5 ml) and anhydrous methanol (10 ml) was stirred under N 2 atmosphere at ambient temperature for 18 hours. The mixture was concentrated to an oil which was chromatographed on silica gel to provide methyl D,L-erythro-epsilon-((4-acetyl-3-(2-methoxy-2-oxoethoxy)phenyl)thio)-delta-hydroxy-4-nonylbenzenehexanoate as an oil.
  • Step 2 A mixture of the diesterfrom Step 1 (1.23 g), THF (20 ml) and 0.2N NaOH (26.2 ml) and methanol (1 ml) was stirred 1 hour at ambient temperature. The mixture was treated as described for Example 58, Step 2, to provide the title compound, as a foam.
  • Step 1 A mixture of ethyl 3-methyl-6-mercapto-2-benzofuran carboxylate (0.61 g), the epoxide from Example 48, Step B, (0.792 g), triethylamine (1.28 ml) and methanol (10 ml) was stirred under N 2 atmosphere for 18 hours. The mixture was concentrated to an oil and chromatographed on silica gel to provide D,L-erythio-methyl 6-((2-hydroxy-6-methoxy-1-(4-nonylphenyl)-6-oxohexyl)thio)-3-methyl-2-benzofurancarboxylate, as an oil.
  • Step 2 A mixture of the ester from Step 1. (1.09 g), THF (24 ml) and 0.2N NaOH (24 ml) and methanol (1 ml) was stirred at ambient temperature for 18 hours. The mixture reduced to dryness, dissolved in water and treated as described in Example 58, Step 2, to provide the title compound, as a foam.
  • Step 1 A mixture of the epoxide from Example 48, Step B, (0.35 g), methyl 6-mercapto-2-oxo-2H-1-benzopyran-3-carboxylate (0.24 g) and triethylamine (0.1 ml) in methanol (10 ml) was stirred at ambient temperature under N 2 atmosphere for 15 hours. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel to yield D,L-erythio-methyl 6-((2-hydroxy-6-methoxy-1-(4-nonylphenyl)-6-oxohexyl)thio)-2-oxo-2H-1-benzopyran-3-carboxylate, as an oil.
  • Step 2 The diester from Step 1 (200 mg) was stirred in THF (10 ml) with 1 N NaOH (1.0 ml), under N 2 for 18 hours. The mixture was concentrated and then purified on XAD-8 resin as described in Example 58, Step 2, to provide the title compound, m.p. 195° (decomp.).
  • Step 1 A mixture of 3-mercaptonalide (125 mg), the epoxide from Example 48, Step B (346 mg), and triethylamine (0.3 ml) in methanol (10 ml) was stirred at ambient temperature for 18 hours. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel to yield the D,L-erythio-methyl epsilon-(3-aminophenylthio)-1-delta-hydroxy-(4-nonylphenyl)hexanoate.
  • Step 2 The mixture of the ester from Step 1 (1 g) and 1 N NaOH (2 ml) in methanol (10 ml) was stirred at ambient temperature for 18 hours. The mixture was concentrated and purified on XAD-8 resin as described in Example 58, Step 2, to provide the title compound as a viscous oil.
  • Step 1 A mixture of the amine from Example 64, Step 1, (2 g) and acetic anhydride (2 ml) in pyridine (25 ml) was stirred at ambient temperature for 18 hours. The volatile components were removed in vacuo and the residue was chromatographed on silica gel to provide (D,L)-erythro-methyl epsilon-((3- acetylamino)phenyl)thio)-delta-hydroxy-(4-nonylbenzenehexanoate as an oil.
  • Step 2 The diacetate from Step 1 was stirred in methanol (25 ml) with 1N NaOH (2 ml) for 18 hours at ambient temperature. The solvents were removed by evaporation and the residue was dissolved in water and purified on a column of XAD-8 resin as described in Example 58, Step 2, to provide the title compound m.p. 200°.
  • Step 1 A mixture of the epoxide from Example 48, Step B, (1.5 g), 3-((3-ethoxy-3- oxopropyl)amino)phenylmercaptan (1 g) and triethylamine (2 ml) in methanol (30 ml) was stirred 18 hours at ambient temperature. The solvents were removed in vacuo and the residue was chromatographed on silica gel to provide D,L-erythio-methyl epsilon-((3-ethoxy-3-oxopropyl)-(3-amino)phenyl)thio)-delta-hydroxy-(4-nonylphenyl)hexanoate as an oil.
  • Step 2 The diester from Step 1 (1 g) in methanol (50 ml) with 1N NaOH (3 ml) was stirred at ambient temperature 18 hours. Workup as described in Example 58, Step 2, provided the title compound as a gum.
  • Step 1 D,L-erythio-methyl-epsilon-((3-((3-methoxy-3-oxopropionyl)amino)phenyl)thio-delta-hydroxy-(4-nonylphenyl)hexanoate
  • Step 2 D,L-Erythro-epsilon-((3-((2-carboxyacetyl)amino)phenyl)thio)--delta-hydroxy-(4-nonylphenyl)hexanoic acid disodium salt hemihydrate
  • Step 1 To a solution of the diester from Example 67, Step 1 (4 g) in dichloromethane (1.4 ml) at 0°, was added m-chloroperbenzoic acid (1.21 g) in CH 2 Cl 2 (100 ml). The mixture was stirred 10 minutes, then calcium hydroxide (3 g) was added, the mixture was stirred 15 minutes, filtered through celite; and the filtrate was evaporated to dryness to yield a residue which was chromatographed on silica gell to yield diastereomer 1 (more polar):
  • Step 2 The more polar diastereomer (isomer 1) from Step 1 (1 g) was stirred with 1 N NaOH (3 ml) and methanol (15 ml) at ambient temperature for 18 hours. Workup as described for Example 58, Step 2, provided one of the title diastereomers, as a hygroscopic monohydrate, m.p. 175 ⁇ 178°.
  • Step 3 The less polar diastereomer (isomer 2) from Step 1 (0.8 g) was stirred with 1N NaOH (3 ml) and methanol (50 ml) was stirred at ambient temperature for 18 hours. Workup as described for Example 58, Step 2, provided the other title diastereomer, as a hygroscopic solid, m.p. 175-178°.
  • Step 1 A mixture of the epoxide from Example 48, Step B, (0.60 g), 3-mercapto-N-formyl-N-(2-ethoxy-2-oxoethyl)analine (0.70 g) and triethylamine (1.4 ml) in methanol (25 ml) was reacted following the procedure described in Example 66, to provide D,L-erythro methyl-epsilon-((3-((2-methoxy-2-oxoethyl)formylamino)phenyl)thio)-delta-hydroxy-(4-nonylphenyl)hexanoate, as an oil;
  • Step 2 The diester from Step 1 (0.8 g), in 1 N NaOH (3 ml) and methanol (25 ml) was reacted following the procedure described in Example 58, Step 2, to provide the title compound, m.p. 270° (decomp.)
  • Step 1 To a solution of the diastereomer 1 from Example 68, Step 1 (1 g) in CH 2 CI 2 (50 ml) was added m-chloroperbenzoic acid (0.3 g) and the mixture was stirred 18 hours at ambient temperature. The mixture was concentrated and the residue was chromatographed on silica gel to provide erythromethyl epsilon-((3-((2-methoxy-2-oxoethyl)amino)phenyl)sulfonyl)-delta-hydroxy-4-nonylbenzenehexanoate as an oil.
  • Step 2 The diester from Step 1 (0.8 g), 1 N NaOH (3 ml) and methanol (50 ml) were reacted following the procedure described in Example 58, Step 2, to provide the title compound as hygroscopic solid, m.p. 175 ⁇ 180°.
  • Step 1 A mixture of 4-mercaptoanaline (250 mg) the epoxide from Example 48, Step B (700 mg) and triethylamine (0.5 ml) in methanol (15 ml) was stirred at ambient temperature for 18 hours. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel to provide D,L-erythro-methyl epsilon-((4-aminophenyl)thio)-delta-hydroxy-(4-nonylphenyl)hexanoate.
  • Step 2 A mixture of the ester from Step 1 (1 g) and 1 N NaOH (2 ml) in methanol (20 ml) was stirred at ambient temperature of 18 hours. The mixutre was concentrated and purified on XAD-8 resin as described in Example 58, Step 2, to provide the title compound, m.p. 180-200°.
  • Step 1 A mixture of the amine from Example 72, (Step 1) (1 g) and acetic anhydride (1 ml) in pyridine (20 ml) was stirred at ambient temperature for 18 hours. The volatile components were removed in vacuo and the residue was chromatographed on silica gel to provide D,L-erythromethyl delta-acetoxy-epsilon-((4- acetylamino)phenyl)thio)-(4-nonylphenyl)hexanoate, which was used directly in the next step.
  • Step 2 The diacetate from Step 1 (1 g) was stirred in methanol (10 ml) and 1 N NaOH (2 ml) for 18 hours. The solvents were removed by evaporation and the residue was dissolved in water and purified on a column of XAD-8 resin as described in Example 58. Step 2, to provide the title compound, m.p. 124 ⁇ 130°.
  • Step 2 A mixture of the thiol from Step 1 (1 g), the epoxide from Example 48, Step B (1.45 g) and triethylamine (1 ml) in methanol (25 ml) was stirred under an N 2 atmosphere, at ambient temperature for 18 hours. The mixture was evaporated to dryness and the residue was chromatographed on silica gel to provide D,L-erythro-methyl epsilon-((4-((3-oxo-3-ethoxypropionyl)amino)phenyl)thio)-delta-hydroxy-(4-nonylphenyl)hexanoate as an oil.
  • Step 3 A mixture of the diester from Step 2 (1.5 g), in NaOH (2 ml) in methanol (10 ml) was stirred at ambient temperature for 18 hours. The mixture was reduced to dryness, the residue was dissolved in water and purified on a column of XAD-8 resin as described in Example 58, Step 2, to provide (D,L)-erythro- epsilon-((4-((carboxyacetyl)amino)phenyl)thio)-delta-hydroxy-(4-nonylphenyl)hexanoic acid disodium salt, m.p. 150°.
  • Step 1 A mixture of the epoxide from Example 48, Step B, (1.38 g), 2-mercaptonanaline (0.5 g) and triethylamine was stirred together for 18 hours at ambient temperature. The solvents were removed by evaporation in vacuo and the residue was purified by chromatography on silica gel to provide D,L-erythro- methyl epsilon-((2-aminophenyl)thio)-delta-hydroxy-(4-nonylbenzene)hexanoate.
  • Step 2 A mixture of the ester from Step 1 (1 g) and 1 N NaOH (2 ml) in methanol (20 ml) was stirred 18 hours at ambient temperature. The solvents were removed in vacuo and the residue was purified on XAD-8 resin as described in Example 58, Step 2, to provide the title compound. m.p. 150°.
  • Step 1 D,L-Erythro-methyl epsilon-(2-((((4-chlorophenyl)methyl)amino)carbonyl)phenyl)thio-delta-hydroxy(4-nonylphenyl)hexanoate
  • Step 2 The diester from Step 1 (2.38 g) was dissolved in methanol (100 ml) and 5N KOH (2.5 ml) and the mixture was stirred under argon atmosphere for 2 days. The mixture was refluxed 6 hours, cooled, concentrated to 20 ml, and diluted with water (50 ml). The solution was acidified with 12N HCI, extracted with CH 2 Cl 2 , and the organic extract was washed with water, dried (MgS0 4 ) and evaporated to dryness to provide a solid which, after trituration with acetonitrile, provided the title compound, m.p. 128-129°.
  • Step 3 The esterfrom Step 2 (471 mg) was stirred in methanol (4 ml) and 5N KOH (0.8 ml) under argon at ambienttemperature for 2 hours. The mixture was acidified with 0.5N HCI and extracted with CH 2 Cl 2 . The organic extracts were reduced to dryness and redissolved in 0.5N NaOH (2 ml). The solution was applied to a column of XAD-8 resin and after standing 1 hour the column was washed with water (1.251). Elution with ethanol provided (after removal of the solvents in vacuo) the title compound, m.p. 88 ⁇ 89°.
  • Step 2 D,L-Erythro-methyl epsilon((3-(cyanoacetylamino)phenyl)thio)delta-hydroxy-4-nonyl- benzenehexanoate
  • Step 4 D,L-Erythro-methyl delta-hydroxy-epsilon-(((5-t-butyldiphenylsiloxy-4-oxo-4H-pyran-2-yl)-methyl)thio-4-nonylbenzenehexanoate
  • Step 1 (+)-Erythro-methyl delta-hydroxy-epsilon-(3-(2-methoxy-2-oxo-ethyl)amino)3-oxo-2-(phenylmethyl)propyl)thio)4-nonylbenzene hexanoates
  • Step 1 Methyl epsilon-((3-((3-ethoxy-1,3-dioxopropyl)amino)phenyl)thio)-4-nonylbenzenehexanoate
  • Step 1 Erythro-methyl epsilon-((3-((3-carboxy-1-oxopcopyl)amino)phenyl)thio)-delta-hydroxy-4-nonylbenzenehexanoate monohydrate
  • Step 2 D,L-Erythro-epsilon-((3-((3-carboxyl-1-oxopropyl)amino)phenyl)thio)-delta-hydroxy-4-nonylbenzenehexanoic acid disodium salt sesquihydrate
  • Step 2 D,L-Epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-delta-oxo-4-nonylbenzenehexanoicacid
  • Step 4 D,L-Methyl erythro-epsilon-((3-((3-methoxy-1,3-dioxopropyl)amino)phenyl)thio)-delta-hydroxy-4-nonylphenylhexanoate
  • Step 5 D,L-erythro-3-((3-(((4-nonylphenyl)(tetrahydro-6-oxo-2H-pyran-2-yl)methyl)thio)phenyl)amino)-3- oxopropanoic acid monohydrate
  • Aluminium chloride (15.0 g) was added in portions to an ice-cold mixture of diphenylmethane (8.4 g), monomethyl adipic acid chloride (8.98 g) and methylene chloride (150 ml). The mixture was stirred 30 minutes at ambient temperature and then poured onto ice. The organic phase was separated, washed with water, dried (MgS0 4 ) and evaporated to an oil. Chromatography on silica provided the title compound, as an oil.
  • Step 5 Methyl erythro-epsilon-((3-methoxy-1;3-dioxopropyl)amino)phenyl)thio)-delta-hydroxy-4-(phenylmethyl)benzenehexanoate
  • Step 6 D,L-Erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-delta-hydroxy-4(phenylmethyl)-benzenehexanoic acid disodium salt trihydrate
  • Step 5 D,L-Erythro-methyl-epsilon-((3-((3-ethoxy-1,3-dioxopropyl)aminolphenyl)thio)1,2-dihydro-delta-hydroxy-5-acenaphthalenehexanoate
  • Step 6 D,L-Erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-1,2-dihydro-delta-hydroxy-5- acenapthalenehexanoic acid disodium slat sesterhydrate
  • Step 4 (E)-Methyl delta, epsilon-epoxy-4(2-phenylethylbenzenehexanoate
  • Step 5 Erythro-methyl delta-hydroxy-epsilon-((3-((3-methoxy-1,3-dioxopropyl)amino)phenyl)thio)-4-(2-phenylethyl)benzenehexanoate
  • Step 6 Erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-delta-hydroxy-4-(2-phenylethyl)benzenehexanoic acid disodium salt dihydrate
  • Step 1 Erythro-methyl 7-((2-hydroxy-6-methoxy-6-oxo-1-(4-(2-phenylethyl)phenyl)hexyl)thio)-2-methoxy-3-quinolinecarboxylate
  • Step2 D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(4-(2-phenylethyl)phenyl)pentyl)thio)-2-methoxy-3-quinolinecarboxylic acid disodium salt dihydrate
  • Step 1 Methyl 5,6,7,8-tetrahydro-epsilon-oxo-2-naphthalene hexanoate
  • Step 4 (E)-Methyl delta, epsilon-epoxy-5,6,7,8-tetrahydronaphthalenehexanoate
  • Step 5 D,L-Erythro-methyl epsilon-((3-((3-methoxy-1,3-dioxopropyl)amino)phenyl)thio)-5,6,7,8-tetrahydro-delta-hydroxy-2-naphthalenehexanoate
  • Step 6 Erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-5,6,7,8-tetrahydro-delta-hydroxy-2-naphthalenehexanoic acid disodium salt sesquihydrate
  • Step 1 Erythro-methyl7-((2-hydroxy-6-methoxy-6-oxo-1-(5,6,7,8-tetrahydro-2-naphthalenyl)hexyl)thio)-2-methoxy-3-quinolinecarboxylate
  • Step2 D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(5,6,7,8-tetrahydro-2-naphthalenyl)pentyl)thio)-2-methoxy-3-quinolinecarboxylic acid disodium salt sesquihydrate
  • the lactone from Step 1 above (600 mg) was stirred in a mixture of THF (20 ml), 2N lithium hydroxide (3 ml) and H 2 O (10 ml). After 10 hours stirring the THF was removed by concentration, the solution was diluted with H 2 0, made strongly acidic with conc. HCI (2 ml) and extracted with CHCl 3 (5 x 20 ml). The CHCl 3 extracts were dried with anhydrous sodium sulphate and filtered. To the CHCI 3 solution was added dicyclohexylamine (540 mg). The solution was then stirred 1 hour, and the CHCI 3 was removed under reduced pressure to yield a white solid, which yielded upon crystallization from ethyl acetate/methanol the title compound, m.p. 152-154°.
  • Step 1 Methyl epsilon-oxo-(3,4-dichlorophenyl)hexanoate
  • the keto ester from Step 1 (8 g) was taken up in methanol (120 ml) to which was added in 3 portions, at room temperature, sodium borohydride (1.6 g). After 20 minutes the reaction was quenched with a saturated solution of ammonium chloride (150 ml) followed by acidification with conc. HCI. The methanol was removed under reduced pressure, and the aqueous solution was extracted with methylene chloride (8 x 50 ml). The residue after concentration was chromatographed on silica gel to yield the title compound.
  • Step 4 (E)-methyl delta,epsilon-epoxy-(3,4-dichlorophenyl)hexanoate
  • Step 5 D,L-Erythro-methyl 7-((1-(3,4-dichlorophenyl)-2-hydroxy-6-methoxy-6-oxohexyl)thio)-4-oxo-4H-1-benzopyran-2-carboxylate
  • Step 6 D,L-Erythro-7-((5-carboxy-1-(3,4-dichlorophenyl)-2-hydroxypentyl)thio)-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt sesquihydrate
  • meta-Bromobenzylbromide 100 g was taken up in toluene (1.5 I) to which was added triphenyl phosphine (100 g). The mixture was refluxed under N 2 for 2.5 hours then stirred at room temperature for 20 hours. The resulting precipitate was filtered to yield the title compound; m.p. 302-304°.
  • the phosphonium salt from Step 1 (150 g) was added to a suspension at 0°C of potassium t-butoxide (33 g) in tetrahydrofuran (1800 ml). After stirring 30 minutes at 0°C under N 2 , octylaldehyde (37.6 g) in tetrahydrofuran (50 ml) was added dropwise. After addition the mixture was warmed to room temperature for 2 hours. Diethyl ether (1 I) was added, the mixture was filtered, washed with water, dried and concentrated. Chromatography on silica gel provided the title compound as an oil.
  • step 2 The olefin from step 2 (30 g) in ethyl alcohol (450 ml) and platinum oxide (500 mg) was reduced with hydrogen at 3 psi for 20 minutes.
  • the catalyst was removed by filtration through a bed of Celite/sodium sulphate and the ethanol was concentrated to yield the title compound as an oil.
  • Step 4 Methyl epsilon-hydroxy-(3-nonylbenzene)hexanoate
  • reaction was quenched with saturated ammonium chloride (120 ml) and then was extracted with diethyl ether (5 x 50 ml). The residue after concentration of the ether extracts was purified on silica gel to provide the title compound as an oil.
  • Step 6 (E)-methyl delta,epsilon-epoxy-(3-nonylbenzene)hexanoate
  • Step 7 D,L-erythro-methyl 7-((2-hydroxy-6-methoxy-1-(3-nonylphenyl)thio)-6-oxohexyl)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Step 8 D,L-erythro-7-(5-carboxy-2-hydroxy-1-(3-nonylphenyl)pentylthio)-4-oxo-8-propyl-4H-1-benzopyran 2-carboxylic acid disodium salt dihydrate
  • Step 1 Methyl D,L-erythro-7-((1-(4-butylphenyl)-6-methoxy-6-oxo-2-hydroxyhexyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Step2 D,L-erythro-7-((1-(4-butylphenyl)-5-carboxy-2-hydroxypentyl)thio)-4-oxo-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt sesquihydrate
  • the phosphonium salt from Step 1 (150 g) was added to a suspension at 0°C of potassium t-butoxide (33 g) in tetrahydrofuran (1800 ml). After stirring for 30 minutes at 0°C under N 2 , a solution of octylaldehyde (37.6 g) in tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was then stirred at room temperature for 15 hours. Diethyl ether (1 I) was added and the mixture was filtered, washed with water, dried and concentrated to provide the title compound as an oil.
  • the olefin from Step 2 (20 mg) was dissolved in ethyl alcohol (140 ml) and platinum oxide (200 mg) was added. The olefin was reduced with hydrogen at 3 psi for 20 minutes. The mixture was filtered through a bed of Celite/sodium sulfate and the filtrate was concentrated to yield the title compound as an oil.
  • Step 7 Methyl D,L-erythro-7-((2-hydroxy-6-methoxy-1-(2-nonylphenyl)-6-oxo-hexyl)thio)4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Step 8 D,L-erythro-7-((5-carboxy-2-hydroxy-1-(2-nonylphenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt dihydrate
  • Step 1 Methyl D,L-erythro-epsilon-((3-((3-methoxy-3-oxopropyl)amino)phenyl)thio)-delta-hydroxy-3-nonylbenzenehexanoate
  • Step2 D,L-erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-delta-hydroxy-3-nonylbenzenehexanoic acid disodium salt monohydrate
  • Step 1 Methyl D,L-erythro-delta-hydroxy-epsilon-(((3-methoxyoxomethyl)phenyl)methyl)thio)-4-nonylbenzenehexanoate
  • Step2 D,L-Erythro-epsilon-(((3-carboxyphenyl)methyl)thio)-delta-hydroxy-4-nonylbenzene-hexanoic acid disodium salt dihydrate
  • Step 1 Methyl D,L-erythro-delta-hydroxy-epsilon-((3-methoxy-1,3-dioxopropyl)amino)phenyl)thio)-4-nonylbenzenehexanoate
  • Step 2 D,L-Erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-delta-hydroxy-4-nonylbenzene- hexanoic acid disodium salt sesterhydrate
  • Step 1 Methyl 7-(((2S,5S),(2S,5R),(2R,5S),(2R,5R)-2-hydroxy-3-(methoxycarbonyl)nonyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Step 2 7-(((2S,5S),(2S,5R),(2R,5S),(2R,5R)-5-Carboxy-2-hydroxynonyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disoium salt monohydrate
  • Step 3 Methyl D,L-7-((6-methoxy-6-oxo-2-((butylthio)methyl)phenyl)hexyl)oxy)-4-oxo-8-propyl-4H,1-benzopyran-2-carboxylate
  • Step 4 7-((5-Carboxy-2-(3-((butylthio)methyl)phenyl)oxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt
  • Step 1 D,L-Methyl 7-((1-3-((butylthio)methyl)phenyl)-6-methoxy-6-oxo-hexyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Triphenylphosphine (1.2 g) was taken up in tetrahydrofuran at 0°C under N 2 . To this solution was added diethylazodicarboxylate (800 mg) with stirring for 30 mins. A mixture of the alcohol from Example 114, Step 2 (740 mg) and methyl 7-mercapto-8-propyl-4-oxo-4H-1-benzopyran-2-carboxylate (700 mg) in tetrahydrofuran (25 ml) was added to the above mixture at 0°C. After stirring 1 hour at room temperature the reaction mixture was concentrated and the residue was chromatographed on silica gel to yield the title compound as an oil.
  • Step2 7-((1-(3-((Butylthio)methyl)phenyl)-5-carboxypentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt
  • Step 1 D,L-Methyl (E)-delta,epsilon-epoxy-4-(1,1-dimethylethyl)benzenehexanoate
  • Step 2 D,L-Erythro-methyl 7-((1-(4-(1,1-dimethylethyl)phenyl)-2-hydroxy-6-methoxy-6-oxohexyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Step 3 D,L-Erythro-7-((5-carboxyl-(4-(1,1-dimethylethyl)phenyl)-2-hydroxypentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate disodium salt monohydrate
  • the diester from Step 2 (715 mg) was stirred in THF (10 ml) and 0.2N NaOH (18.4 ml) at ambient temperature for 18 hours. The mixture was concentrated in vacuo to remove the THF and applied to a column of Amberlite XAD-8 resin. The column was washed with water until the effluent was neutral. Eluting with ethanol gave after concentration to dryness, the title compound, as a foam.
  • Methyl 4-(chloroformyl)butyrate (15.2 ml) was added to a stirred suspension of anhydrous aluminum chloride (32 g) in anhydrous 1,2-dichloroethane and the mixture was stirred under N 2 atmosphere at ambient temperature for 15 minutes.
  • n-phenyloctane (15.2 ml) was added slowly and after 30 minutes the mixture was poured into water and ice.
  • the mixture was extracted with CH 2 Cl 2 (2 x 100 ml) and the combined organic phases were washed with brine, dried (Na 2 SO 4 ) and reduced to dryness to provide the title compound, as an oil.
  • This oil was dissolved in toluene (200 ml) and hydrated p-toluenesulfonic acid (1.8 g) was added. The mixture was stirred at ambient temperature and after 45 minutes the mixture was evaporated to dryness and the residue was chromatographed on silica gel to provide the title compound.
  • Step 4 Methyl (E)- and (Z)-zeta-hydroxy-(4-octylphenyl)hept-alpha-enoates
  • Step 7 Methyl (E)-epsilon,zeta-epoxy-4-octylbenzene-hept-epsilon-enoate
  • Step 8 D,L-Erythro-methyl 7-((2-hydroxy-7-methoxy-1-(4-octylphenyl)-7-oxoheptyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
  • Step 9 D,L-Erythro-7-((6-carboxy-2-hydroxy-1-(4-nonylphenyl)hexyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt
  • Step 1 D,L-Erythro-methyl epsilon-hydroxy-zeta-((3-((3-methoxy-1,3-dioxypropyl)amino)phenyl)thio)-4-octylbenzeneheptanoate
  • Step 2 (Epsilon S, zeta R) and (epsilon R, zeta S)-zeta-3-((((carboxyacetyl)amino)phenyl)thio)epsilon- hydroxy-4-nonylbenzeneheptanoic acid disodium salt
  • the diester from Step 1 (315 mg) was stirred in THF (10 ml) and 0.2N NaOH (5.8 ml) at ambient temperature for 18 hours. The mixture was concentrated in vacuo to remove the THF and then purified on a column of amberlite XAD-8 resin as described in Example 117, Step 3 to provide the title compound, as a foam.
  • Step 3 Methyl delta(S), epsilon(R)-delta, epsilon-epoxy-(2(E)-(4-octylphenyl)ethenyl)hexanoate
  • Step 5 7-((5-Carboxy-2(S)-hydroxy-1 (R)-(2(E)-(4-octylphenyl)ethenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt hydrate
  • Step 2 D,L-Erythro-methyl 7-((1-(4-butylphenyl)-2-hydroxy-6-methoxy-6-oxohexyl)thio)-4-methyl 2-oxo-8-propyl-2H-1-benzopyran-3-acetate
  • the diester from Step 2 (771 mg) was stirred in THF (10 ml) and 0.2N NaOH 93 ml) at ambient temperature for 18 hours. The mixture was concentrated to remove the THF and then purified on a column of Amberlite XAD-8 resin as described in Example 117, Step 3 to provide the title compound, as a foam.
  • Step 4 D,L-Methyl delta, epsilon-(E)-epoxy-(2(E)-(4-octylphenyl)ethenyl)hexanoate
  • Step 6 D,L-(E)-Erythro-7-((5-carboxy-2-hydroxy-1-(2-(4-octylphenyl)ethenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid disodium salt dihydrate
  • the diester from Step 5 (138 mg) was stirred in THF (10 ml) and 0.2N NaOH (2.3 ml) at ambient temperature for 18 hours. The mixture was concentrated in vacuo to remove the THF and then purified on a column of Amberlite XAD-8 resin as described in Example 117, Step 3 to provide the title compound, as a foam.
  • Step 1 D,L-Methyl delta, epsilon(E)-epoxy-(2-(E)-phenylethenyl)hexanoate
  • Tetrahydrothiophene (8.6 ml) was added to a suspension of cinnamyl bromide (16 g) in a mixture of methanol (80 ml) and water (8 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo to remove the solvent and the residue was dissolved in dichlorometane (120 ml). Methyl 4-formylbutyrate (11.6 g, 65% pure) and triethylbenzylammonium chloride (0.60 g) were added. The mixture was cooled to -30°C, 10N NaOH (100 ml) was added and the mixture was vigorously stirred for 5 minutes.
  • Step 1 D,L-(E)-Erythro-methyl 5-hydroxy-6-((3-((3-methoxy-1,3-dioxopropyl)phenyl)thio)-8-phenyl-7- octenoate
  • Step 6 D,L-Erythro-epsilon-((3-((carboxyacetyl)amino)phenyl)thio)-delta-hydroxy-4-phenoxy- benzenehexanoic acid

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Claims (13)

1. Verbindungen der Formel
Figure imgb0058
und Verbindungen, die pharmazeutisch annehmbare Salze davon sind, worin
X 0 oder S ist;
jedes n 0 bis 2 ist, wie gefordert, um vier Bindungen für den entsprechenden Kohlenstoff zu gewährleisten;
a 0 oder 1 ist; die gestrichelten Linien gegebenenfalls vorhandene Doppel- und Dreifachbindungen darstellen;
jedes von b und c unabhängig vom anderen, 0 oder eine ganze Zahl von 1 bis 5 ist;
R' COOR2, CH2OH, CHO, Tetrazol, Hydroxymethylketon, CN, CONR2R4, ein monocyclischer oder bicyclischer heterocyclischer Ring, enthaltend eine saure Hydroxylgruppe oder NHS02R4, ist oder ein Rest der Formel
Figure imgb0059
 worin jedes s, unabhängig vom anderen, 0, 1, oder 3 ist; jedes R14 unabhängig ein Wasserstoffatom oder ein geradkettiger oder verzweigter C1-4-Alkylrest; und R15 (A) ein monocyclischer oder bicyclischer heterocyclischer Rest mit 3 bis 12 Kernkohlenstoffatomen, einem Kernstickstoff-Heteroatom und gegebenenfalls einem Schwefel- oder einem zweiten Stickstoff-Heteroatom, wobei jeder Ring im heterocyclischen Rest aus 5 oder 6 Atomen gebildet wird; oder (B) ein Rest W―R16 ist, worin W, O, S oder NH ist und R16 bis zu 21 Kohlenstoffatome in geradkettiger oder verzweigter Anordnung enthält, und (1) ein Kohlenwasserstoffrest oder (2) ein Acylrest einer organischen acyclischen oder monocyclischen Carbonsäure mit nicht mehr als einem Heteroatom ausgewählt aus N, O oder S im Ring ist;
R4 Wasserstoff; Alkyl; Hydroxyl; Halogen; Halogenalkyl; Benzyl; mit wenigstens einem R7 substituiertes Benzyl, worin R7 H, Alkylthioalkyl, Alkylthiobenzyl oder Alkylthioaryl ist; Aryl; mit wenigstens einem R5 substituiertes Aryl; NO2; CN; SCR3; OR5; O-Benzyl, mit wenigstens einem R5 substituiertes 0-Benzyl; O-Aryl; mit wenigstens einem R5 substituiertes O-Aryl; SR5, NR2R5, SOR5 oder SO2R5 ist; worin R5 H; Alkyl; Hydroxyl; Halogen; Halogenalkyl; Benzyl; mit wenigstens einem R3 substituiertes Benzyl; NO2; CN; SCF3; OR3, O-Benzyl; mit wenigstens einem R3 substituiertes O-Benzyl; O-Aryl; mit wenigstens einem R3 substituiertes O-Aryl; SR3; NR2R3; SOR3 oder SO2R3 ist;
jedes R2 und R3 unabhängig von dem oder jedem anderen Wasserstoff oder Alkyl ist;
A H,
Figure imgb0060
ist, worin die gestrichelte Linie anzeigt, daß gegebenenfalls eine Doppelbindung vorhanden ist, und R4, R5 und R7 wie oben definiert sind;
B H
Figure imgb0061
Figure imgb0062
Figure imgb0063
Figure imgb0064
ist, worin R1, R2, R4 und a wie oben definiert sind; R3 H, nieder-Alkyl, Halogen, OR2, SR2, SOR4 oder S02R 5 ist, worin R2, R4 und R5 wie oben definiert sind;
Z H, NHR9, NR2R9, eine N-terminal gebundene essentielle Aminosäure oder ein nieder-Alkylester davon, OH, OR4 oder OR2, ist, worin R2 und R4 wie oben definiert sind;
Figure imgb0065
worin R1, R2 und R3 wie oben definiert sind, d 0 oder 1 ist e 0 bis 9 ist, f und g unabhängig 0, 1, 2 oder 3 sind und d+e+f+g≥1 ist;
R9 H,
Figure imgb0066
ist;
R10
Figure imgb0067
ist, worin d 0 oder 1 ist, e 0 bis 9 ist, f und g unabhängig 0, 1, 2 oder.3 sind und R1, R2 und R3 wie oben definiert sind;
R11 Z ist, wenn d 1 ist, und R1 oder Z ist, worin R1 und Z wie oben definiert sind, wenn d 0 ist; und
R12 H, Acyl, Formyl, CN oder SO2R13 ist, worin
R13 H, Alkyl oder Aryl ist; und
Y H oder OH ist, mit der Maßgabe, daß, wenn Y OH ist, A
Figure imgb0068
ist, B eines aus (3), (4), (5) und (6) ist.
2. Verbindung, wie in Anspruch 1 beansprucht, worin n, b, c, R2, R3, R4 und die gestrichelten Linien wie in Anspruch 1 definiert sind, A
Figure imgb0069
ist
R1 COOR2, CH2OH, CHO, Tetrazol, Hdroxymethylketon, CN, CONR2R4 oder ein monocyclischer oder bicyclischer heterocyclischer Ring, enthaltend eine sauer Hydroxylgruppe oder NHSO2R4, ist;
R5 H; Alkyl; Hydroxyl; Halogen; Halogenalkyl; Benzyl; mit wenigstens einem R3 substituiertes Benzyl; NO2; CN; SCF3; OR3; O-Benzyl; mit wenigstens einem R3 substituiertes O-Benzyl; O-Aryl; mit wenigstens einem R3 substituiertes O-Aryl; SR3; NR2R3; SOR3 oder SO2R3 ist;
R7 H; Alkylthioalkyl; Alkylthiobenzyl oder Alkylthioaryl ist;
Y H oder OH ist;
X O oder S ist;
B H;
Figure imgb0070
Figure imgb0071
Figure imgb0072
Figure imgb0073
ist, worin
Z H, NHR9, NR2R9 eine N-terminal gebundene essentielle Aminosäure oder ein nieder-Alkylester davon, OH, OR4 oder OR2 ist;
R6 H, nieder-Alkyl, Halogen, OR2 oder SR2 ist;
R8 H, nieder-Alkyl oder ―(CH2)aR1 ist;
R9 H,
Figure imgb0074
ist;
R10
Figure imgb0075
ist, worin e 0 bis 9 ist und f und g unabhängig 0 bis 3 sind;
R11 Z ist, worin Z wie oben definiert ist, wenn d 1 ist und R", R1 oder Z ist, worin Z wie oben definiert ist, wenn d 0 ist;

wobei jedes a in den oben genannten Definitionen unabhängig 0 bis 5 ist und jedes d in den oben genannten Definitionen 0 oder 1 ist.
3. Verbindungen der Formel I nach Anspruch 1, worin
A
Figure imgb0076
ist und B
Figure imgb0077
Figure imgb0078
ist, worin a, R', R4, R5, R6, R8, R10 und R'2 wie in Anspruch 1 definiert sind.
4. Die Verbindungen:
D,L-Erythro-6-(2-carboxyethylthio)-5-hydroxy-6-pehnyl-hexansäure-bis(dicyclohexylammonium)salz;
5S,6R- und 5R,6S-5-Hydroxy-6-S-(N-trifluoroacetylglutathionyl)hexansäuretrimethylester;
Methyl-e-(butylthio)-(4-nonylbenzol)hexanoat;
Natrium-ε-(phenylthio)-4-nonylbenzolhexanoat;
Methyl-ε-((2-carboxyethyl)thio)-4-nonylbenzolhexanoat;
Methyl-ε-((3-methoxy-3-oxo-propyl)thio)-4-nonylbenzolhexanoat;
ε-((2-Carboxyethyl)thio)-4-nonylbenzolhexansäure;
ε-((3-Methoxy-3-oxopropyl)thio)-4-nonylbenzolhexansäure;
Methyl-7-((6-methoxy-6-oxo-1-(4-nonylphenyl)hexyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylat;
7-(5-Carboxy-1-(4-nonylphenyl)pentyl)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz- monohydrat;
Methyl-7-((6-methoxy-6-oxo-1-(4-nonylphenyl)hexyl)thio-4-oxo-4H-1-benzopyran-2-carboxylat;
7-(5-Carboxy-1-(4-nonylphenyl)pentyl)thio-4-oxo-4H-1-benzopyran-2-carbonsäure-dinatriumsalzhemi- hydrat;
Methyl-7-(5-carboxy-1-(4-nonylphenyl)pentyl)thio-8-propyl-4-oxo-4H-1-benzopyran-2-carboxylat;
ε-(S)- und e-(R)-e-(L-Cysteinyl)-(4-n-nonyl)phenyl-hexansäure;
e-(S)- und ε-(R)-ε-L-Cysteinylglycyl- (4-n-nonylphenyl)-hexansäure-dinatriumsalz;
D,L-((3-Amino-3-oxopropyl)thio)-(4-n-nonyl)phenyl)-hexansäure-natriumsälz;
Methyl-4-nonyl-ε-((2-((trifluoracetyl)amino)ethyl)thio)-benzolhexanoat;
ε-((4-Acetyl-3-hydroxyphenyl)thio)-4-nonylbenzolhexansäure-natriumsalz;
Methyl-ε-((3-carboxyphenyl)thio)-4-nonylbenzolhexanoat;
ε-((3-Carboxyphenyl)thio)-4-nonylbenzolhexansäure;
D,L-e-((4-Carboxyphenyl)thio)-4-nonylbenzolhexansäure;
D,L-7-(5-Carboxy-1-(4-nonylphenyl)pentyloxy)-4-oxo-4H-1-benzopyran-2-carbonsäure-dinatriumsalz;
D,L-Methyl-e-(2,4-dinitro-5-fluorphenoxy)-4-nonylbenzolhexanoat;
D,L-ε-(5-((2-Carboxyethyl)amino)-2,4-dinitrophenoxy)-4-nonylbenzolhexansäure;
D,L-e-(5-Mercapto-2,4-dinitrophenoxy)-4-nonylbenzolhexansäure-monohydrat;
D,L-ε-Hydroxy-(5-decylthiophen-2-)hexansäure;
D,L-Methyl-e-(butylthio)-5-decyl-2-thiophenhexanoat;
D,L-e-(Butylthio)-5-decyl-2-thiophenhexansäure;
D,L-Methyl-ε-(phenylthio)-5-decyl-2-thiophenhexanoat;
D,L-e-(Phenylthio)-5-decyl-2-thiophenhexansäure;
D,L-Methyl-ε-((2-aminophenyl)thio)-5-decyl-2-thiophenhexanoat;
ε-((2-Aminophenyl)thio)-5-decyl-2-thiophencarbonsäure-monohydrat;
D,L-ε-((4-Carboxyphenyl)thio)-5-decyl-2-thiophenhexansäure;
D,L-Methyl-7-(((6-methoxy-6-oxo-1-(5-decyl-2-thienyl))-xyl)thio)-8-propyl-4-oxo-4H-1-benzopyran-2-carboxylat;
D,L-7-(((5-Carboxy-1-(5-decyl-2-thienyl))pentyl)thio)-8-propyl-4-oxo-4H-1-benzopyran-2-carbonsäure;
D,L-Erythro-ε-((2)carboxyethyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure;
D,L-Threo-ε-((2-carboxyethyl)thio)-ε-hydroxy-4-nonylbenzolhexansäure-dinatriumsalz;
N-Y-L-glutamyl-S-(D,L-erythro-5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)-L-cysteinylglycin- trinatriumsalz-tri hydrate;
Methyl-D,L-erythro-ε-((2(L)-((4(L)-amino-5-methoxy-1,5-dioxopentyl)amino)-3-((2-methoxy-2-oxoethyl)amino-3-oxopropyl)thio-δ-hydroxy-4-nonylbenzolhexanoat;
D,L-Erythro-ö-hydroxy-e-(methylthio)-4-nonylbenzolhexansäure, Methyl-D,L-erythro-δ-hydroxy-4-(methylsulfinyl)-4-nonylbenzolhexanoat;
S-((D und L)-Erythro-ε-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)-L-cysteinylglycin-dinatriumsalz;
D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-dihydrat;
D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio-4-oxo-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-trihydrat;
D,L-Threo-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-monoammoniumsalz-monohydrat;
D,L-Erythro-ε-((4-acetyl-3-hydroxyphenyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure-natriumsalz;
Natrium-(D,L)-ε-((4-acetyl-3-hydroxyphenyl)thio)-δ-hydroxy-4-nonylbenzolhexanoat-monohydrat;
D, L-Erythro-natrium-δ-hydroxy-ε-((2-hydroxymethyl)-4-oxo-4H-1-benzopyran-7-yl)thio)-4-nonyl- benzolhexanoatsesquihydrat;
D,L-Erythro-ε-((4-acetyl-3-(carboxymethoxy)phenyl)thio)-δ-hydroxy-4-nonyl-benzol hexansäuredinatriumsalz;
D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-2-methyl-2-benzofurancarbon- säure-dinatriumsalz;
D,L-Erythro-6-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-2-oxo-2H-1-benzopyran-3-carbonsäure-dinatriumsalz-sesquihydrat;
Natrium-(D,L)-erythro-ε-(3-aminophenylthio)-δ-hydroxy-(4-nonylphenyl)hexanoat;
Erythro-natrium-ε-((3-acetylamino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexanoat;
Erythro-ε-((3-((2-carboxyethyl)amino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure-dinatriumsalz;
D,L-Erythro-ε-((3-((2-carboxyacetyl)amino)phenyl)thio)-δ-hydroxy-(4-nonylphenyl)hexansäure- dinatriumsalz-hemihydrat;
die zwei diastereomeren Erythro-ε-((3-((carboxyacetyl)-amino)phenyl)sulfinyl)-δ-hydroxy-4-nonyl- benzolhexansäure-dinatriumsalze;
Erythro-ε-((3-((carboxymethyl)amino)phenyl)thio-δ-hydroxy-4-nonylbenzolhexansäure-dinatriumsalz- monohydrat;
Erythro-ε-((3-((carboxymethyl)formylamino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure- dinatriumsalz;
Erythro-ε-((3-((carboxyacetyl)amino)phenyl)sulfonyl)-δ-hydroxy-4-nonylbenzolhexansäure-dinatriumsalz-trihydrat;
Erythro-natrium-ε-((4-aminophenyl)thio-δ-hydroxy-4-nonylbenzolhexanoat-hemihydrat;
D,L-Erythro-natrium-ε-((4-acetylamino)phenylthio)-δ-hydroxy-(4-nonylphenyl)hexanoat;
D,L-Erythro-ε-((4-carboxyacetyl)amino)phenyl)thio)-δ-hydroxy-(4-nonylphenyl)hexansäure-dinatriumsalz;
(D,L)-Erythro-natrium-ε-((2-aminophenyl)thio)-δ-hydroxy-(4-nonylbenzol)hexanoat-monohydrat;
D,L-Erythro-natrium-e-(((2-acetylamino)phenyl)thio)-ö-hydroxy-(4-nonylbenzol)hexanoat;
D,L-Erythro-ε-((2-((2-carboxyacetyl)amino)phenyl)thio)-δ-hydroxy-(4-nonylphenyl)hexanoat- dinatriumsalz-dihydrat;
Erythro-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-2-naphthalincarbonsäure-dinatriumsalz;
Erythro-6-(5-carboxy-2-hydroxy-1-(4-n-nonylphenyl)pentyl)thio)naphthalin-2-carbonsäure-dinatriumsalz-pentahydrat;
Erythro-(D,L)-natrium-ε-((2-((4-chlorphenyl)methyl)amino)carbonyl)phenylthio-δ-hydroxy-(4-nonyl- benzol)hexanoat;
(+)-Erythro-2-methoxy-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-3-chinolin- carbonsäure;
D,L-Erythro-5-methyl-2-oxo-1,3-dioxoi-4-yl-7-((2-hydroxy-6-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-1-(4-nonylphenyl)-6-oxohexyl)thio)-2-methoxy-3-chinolincarboxylat;
(+)-Erythro-2-butoxy-7-((5-carboxy-2-hydroxy-1-(4-nonylphenyl)pentyl)thio)-3-chinolincarbonsäure;
D,L-Erythro-natrium-ε-hydroxy-e-((3-((3-hydroxy-1-oxo-propyl)amino)phenyl)thio)-4-nonylbenzo hexanoat;
ε-D,L-Erythro-((3-(cyanoacetylamino)phenyl)thio)-δ-hydroxyl-4-nonylbenzolhexansäure-natriumsalz;
D,L-Erythro-δ-hydroxy-P,-(((5-hydroxy-4-oxo-4H-pyran-2yl)methyl)thio)-4-nonylbenzolhexansäure- dinatriumsalz;
(+)-Erythro-e-((3-((carboxymethyl)amino)-3-oxo-2-(phenylmethyl)propyl)thio)-δ-hydroxy-4-nonyl- benzolhexansäure-dinatriumsalz-hemihydrat (Isomer I);
Erythro-ε-((3-carboxycarbonyl)amino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure-dinatriumsalz;
D,L-ε-((3-((carboxyacetyl)amino)phenyl)thio)-4-nonylbenzolhexansäure-dinatriumsalz;
Erythro-ε-((3-((2-carboxy-1-oxypropyl)amino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexanoat- dinatriumsalz-monohydrat (Gemisch von Diastomeren);
D,L-Erythro-ε-((3-((3-carboxyl-1-oxopropyl)amino)phenyllthio)-δ-hydroxy-4-nonylbenzolhexansäure- dinatriumsalz-sesquihydrat;
D,L-ε-((3-((carboxyacetyl)aminophenyl)thio)-δ-oxo-4-nonylbenzolhexansäure;
D,L-Erythro-3-((3-(((4-nonylphenyl)-{tetrahydro-6-oxo-2H-pyran-2-yl)methyl)thio)phenyl)amino)-3- oxopropansäuremonohydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)methylamino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure- dinatriumsalz-monohydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)amino)phenyl)thio)-δ-hydroxy-4-(phenylmethyl)benzolhexansäure- dinatriumsalz-trihydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)amino)phenyl)thio)-1,2-hydroxy-δ-hydroxy-5-acenaphthalinhexan- säure-dinatriumsalz-sesterhydrat;
D,L-Erythro-7-((5-carboxy-1-(1,2-dihydro-5-acenaphthylenyl)-2-hydroxyphenyl)thio)-2-methoxy-3-chinolincarbonsäure-dinatriumsalz-trihydrat;
D,L-Erythro-3-((3-(((1,2-dihydro-5-acenaphthenyl)tetrahydro-6-oxo-2H-pyran-2-yl)methyl)thio)phenyl)amino)-3-oxopropansäure-sesquihydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)amino)phenyl)thio)-ε-hydroxy-4-(2-phenylethyl)benzolhexansäure- dinatriumsalz-dihydrat;
D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(4-(2-phenylethyl)phenyl)pentyl)thio)-2-methoxy-3-chinolin- carbonsäure-dinatriumsalz-dihydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)amino)phyenyl)thio)-5,6,7,8-tetrahydro-δ-hydroxy-2-naphthalin- hexansäure-dinatriumsalz-sesquihydrat;
D,L-Erythro-7-((5-carboxy-2-hydroxy-1-(5,6,7,8-tetrahydro-2-naphthalenyl)pentyl)thio)-2-methoxy-3-chinolincarbonsäure-dinatriumsalz-sesquihydrat;
D,L-6-((2-Carboxyethyl)thio)-5-hydroxyhexansäure-bis(dicyclohexylamin)salz;
D,L-Erythro-7-((5-carboxy-1-(3,4-dichlorphenyl)-2-hydroxypentyl)thio)-4-oxo-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-sesquihydrat;
D,L-Erythro-7-(5-carboxy-2-hydroxy-1-(3-nonylphenyl)pentylthio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-dihydrat;
D,L-Erythro-7-((1-(4-butylphenyl)-5-carboxy-2-hydroxypentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-sesquihydrat;
D,L-Erythro7-((5-carboxy-2-hydroxy-1-(2-nonylphenyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-dihydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)amino)phenyl)thio-δ-hydroxy-3-nonylbenzolhexansäure-dinatriumsalz-monohydrat;
D,L-Erythro-ε-((3-((carboxyacetyl)amino)phenyl)thio)-δ-hydroxy-4-nonylbenzolhexansäure-dinatriumsalz-sesterhydrat;
(2S,5S),(2S,5R),(2R,5S),(2R,5R)-2-Butyl-6-((3-carboxyacetyl)amino)phenyl)thio)-5-hydroxyhexansäure- dinatriumsalz-monohydrat;
7-(((2S,5S),(2S,5R),(2R,5S)-(2R,5R)-5-Carboxy-2-hydroxynonyl)thio)-4-oxo-8-propyl-4H-1-benzopyranyl-2-carbonsäure-dinatriumsalz-monohydrat;
D,L-7-((5-Carboxy-2-(3-((butylthio)methyl)phenyl)pentyl)oxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz;
(2S,5S),(2R,5S),(2R,5S),(2R,5R)-2-Butyl-6-((3-carboxyacetyl)amino)phenyl)thio)-5-hydroxyhexansäure- dinatriumsalz-monohydrat;
7-(((2S,5S),(2S,5R),(2R,5S)-(2R,5R1-5-Carboxy-2-hydroxynonyl)thio)-4-oxo-8-propyl-4H-1-benzopyranyl-2-carbonsäure-dinatriumsalz-monohydrat;
D,L-7-((5-Carboxy-2-(3-((butylthio)methyl)phenyl)pentyl)oxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz;
D,L-7-((1-(3-((butylthio)methyl)phenyl)-5-carboxypentyl)thiol-4-oxo-8-propyl-4H-1-benzopyra n-2-carbonsäure-dinatriumsalz;
D,L-Erythro-7-((5-carboxy-1-(4-(1,1-dimethylethyl)phenyl)-2-hydroxypentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylat-dinatriumsalz-monohydrat;
D,L-Erythro-7-((6-carboxy-2-hydroxy-1-(4-nonylphenyl)hexyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz;
(e-S, i;-R)-und (e-R, ζ-S)-ζ-3-((((Carboxyacetyl)amino)phenyl)thio)-ε-hydroxy-4-nonylbenzolheptan- säure-dinatriumsalz;
7-((5-Carboxy-2(S)-hydroxy-1(R)-2(E)-(4-octylphenyl)ethenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz;
D,L-Erythro-7-((1-(4-butylphenyl)-5-carboxy-2-hydroxypentyl)thio)-4-methyl-2-oxo-2H-1-benzopyran-2- essigsäure-dinatriumsalz-monohydrat;
D,L-(E)-Erythro-7-((5-carboxy-2-hydroxy-1-(2-(4-octylphenyl)ethenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-dihydrat;
D,L-(E)-Erythro-7-((5-carboxy-2-hydroxy-1-(2-phenylethenyl)pentyl)thio)-4-oxo-8-propyl-4H-1-benzopyran-2-carbonsäure-dinatriumsalz-monohydrat;
D,L-(E)-Erythro-6-((3-((carboxyacetyl)amino)phenyl)thio)-5-hydroxy-8-phenyl-7-octensäure-dinatriumsalz-sesquihydrat;
(E)-(5(S),6(R); und 5(R),6(S)-6-((3-((carboxyacetyl)amino)phenyl)thio)-5-hydroxy-8-(4-octylphenyl)-7- octensäure-dinatriumsalz-monohydrat;
(D,L-Erythro-ε-((3-(carboxyacetyl)amino)phenyl)thio)-δ-hydroxy-4-phenoxybenzolhexansäure.
5. Pharmazeutische Zusammensetzung, enthaltend eine pharmazeutisch wirksame Menge einer Verbindung, wie in einem der Ansprüche 1 bis 4 beansprucht, und einen pharmazeutisch annehmbaren Träger.
6. Pharmazeutisch Zusammensetzung, enthaltend eine als Leukotrien-Antagonist wirksame Menge einer Verbindung, wie in einem der Ansprüche 1 bis 4 beansprucht, und zusätzlich enthaltend eine wirksame Menge eines zweiten aktiven Bestandteils, ausgewählt aus der Gruppe, bestehend aus nichtsteroiden, entzündungshemmenden Mitteln; peripher wirkenden Analgetika; Cyclooxygenaseinhibitoren; Leukotrienantagonisten; Leukotrieninhibitoren; H2-Rezeptor-Antagonisten; Antihistaminika; Prostaglandinantagonisten; und Thromboxanantagonisten.
7. Zusammensetzung, wie in Anspruch 6 beansprucht, worin das Gew.-Verhältnis der Verbindung nach Anspruch 1 zum zweiten aktiven Bestandteil im Bereich von 200:1 bis 1:200 liegt.
8. Zusammensetzung nach Anspruch 6 oder 7, worin der zweite aktive Bestandteil Indomethacin ist.
9. Zusammensetzung, wie in Anspruch 5 beansprucht, zur Verwendung bei der Verhütung der Synthese, der Wirkung und/oder der Freisetzung von SRS-A und der Leukotriene C4, D4, E4 und/oder des Leukotriens B4 in Säugetieren, insbesondere im Menschen.
10. Verfahren zur Herstellung von Verbindungen mit der Formel
Figure imgb0079
durch Reagieren einer Verbindung mit der Formel
Figure imgb0080
mit einer Verbindung mit der Formel HS―B in Gegenwart einer Base, ausgewählt aus Triethylamin oder Natriumhydrid, worin die Variablen wie in Anspruch 1 definiert sind.
11. 7 - ((5 - Carboxy - 2(S) - hydroxy - 1 (R) - (2(E) - (4 - octylphenyl)ethylen)pentyl)thio) - 4 - oxo - 8 - propyl - 4H - 1 - benzopyran - 2 - carbonsäure - dinatriumsalz.
EP84302720A 1983-04-21 1984-04-19 Leukotrienantagonisten, deren Herstellung und Verwendung sowie diese enthaltende Zusammensetzungen Expired EP0123543B1 (de)

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KR102268357B1 (ko) 2013-01-29 2021-06-23 아벡신 에이에스 항염증성 및 항종양성 2-옥소티아졸 및 2-옥소티오펜 화합물
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